The anthraquinone ring is present in many classes of antitumor agents including the anthracyclines, mitoxanthrone, and the recently discovered dynemicin A. In the case of mitoxantrone, intercalation of the anthraquinone ring into DNA and the external binding of the side chains are believed responsible for the antitumor activity of this drug. Additionally, intercalation of the anthraquinone portion of dynemicin A would serve to place the reactive enediyne moiety in position for strand cleavage. The utility of the anthraquinone ring as a vehicle for pharmacophores in these and other drugs prompted an investigation of the pyrimido[4,5-g]quinazolines as anthraquinone mimics. Presented herein are the synthesis, physical chemistry, and antitumor properties of these mimics.
The pyrimido[4,5-g]quinazoline-tetrone (quinone) systems were designed as reductive alkylating agents. Reductive alkylation involves the formation of an alkyating quinone methide species upon reduction of the quinone and elimination of a leaving group. Thus, reduction of the quinone would be followed by elimination of leaving group(s) to afford quinone methide species. Kinetic studies show that the quinone methide species formed in solution are capable of activity as nuceophile and electrophile traps. This finding is consistent with our previous studies of quinazoline-based quinone methides (See: Lemus, R. L. et al., J. Org. Chem. 1988, 53, 6099).
The interest in reductive alkylating agents stems from the possibility of selective activation of such agents in low reduction potential tumor cells (See: Keyes et al., Adv. Enz. Reg., 1985, 23, 291). However, the major drawback of these agents is the production of cardiotoxic oxygen radicals (See: Doroshow, J. H., Cancer Res. 1983, 43, 460; and Begleiter, A., Cancer Res., 1983, 43, 481), which result from cycling between the quinone and hydroquinone form of the agent. The pyrimido[4,5-g]quinazoline-tetrone mimics of the present invention are designed to remedy this problem. Reduction affords a hydroquinone stablized by internal hydrogen bonds (See: Skibo, E. B. et al., J. Org. Chem. 1988, 53, 420). The present invention provides kinetic evidence that such a hydroquinone is relatively stable to oxygen because of these hydrogen bonds.
The pyrimido[4,5-g]quinazoline diones were designed as non-redox-active antitumor agents. These analogues are much less reactive than the tetrone reductive alkylating agents and can only trap nucleophiles. For these reasons, the pyrimido[4,5-g]quinazoline diones exhibit cytotoxicity against human cancer cell lines while the tetrones (quinones) are inactive.
The present study of pyrimido[4,5-g]quinazoline based anthraquinone mimics demonstrates the value of preliminary physical studies (kinetics and electrochemistry) in the design of cytotoxic alkylating agents.